EP3103440A1 - Solid dispersions of coenzyme q10 - Google Patents

Solid dispersions of coenzyme q10 Download PDF

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Publication number
EP3103440A1
EP3103440A1 EP15171943.2A EP15171943A EP3103440A1 EP 3103440 A1 EP3103440 A1 EP 3103440A1 EP 15171943 A EP15171943 A EP 15171943A EP 3103440 A1 EP3103440 A1 EP 3103440A1
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Prior art keywords
coenzyme
solid dispersion
dispersion according
polymers
cellulose
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EP15171943.2A
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German (de)
French (fr)
Inventor
Daniele Ciceri
Federico Peterlongo
Massimo Ronchi
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Indena SpA
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Indena SpA
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Priority to EP15171943.2A priority Critical patent/EP3103440A1/en
Priority to CA2988478A priority patent/CA2988478C/en
Priority to SI201630621T priority patent/SI3307244T1/en
Priority to JP2017563338A priority patent/JP6910309B2/en
Priority to HUE16732249A priority patent/HUE047668T2/en
Priority to PL16732249T priority patent/PL3307244T3/en
Priority to ES16732249T priority patent/ES2768950T3/en
Priority to KR1020177035183A priority patent/KR20180017016A/en
Priority to PT167322494T priority patent/PT3307244T/en
Priority to US15/579,975 priority patent/US10905657B2/en
Priority to CN201680032963.7A priority patent/CN107750158B/en
Priority to BR112017026291-6A priority patent/BR112017026291B1/en
Priority to EP16732249.4A priority patent/EP3307244B1/en
Priority to AU2016274662A priority patent/AU2016274662B2/en
Priority to DK16732249.4T priority patent/DK3307244T3/en
Priority to PCT/EP2016/063262 priority patent/WO2016198576A1/en
Priority to RU2017142563A priority patent/RU2742579C2/en
Publication of EP3103440A1 publication Critical patent/EP3103440A1/en
Priority to IL256159A priority patent/IL256159B/en
Priority to HK18110196.1A priority patent/HK1250652A1/en
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/55—Phosphorus compounds
    • A61K8/553—Phospholipids, e.g. lecithin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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Definitions

  • the obtained solid dispersions were analyzed for HPLC content of Coenzyme Q 10 , for water content and for residual solvent.

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Abstract

The invention relates to a solid dispersion comprising Coenzyme Q10 and a phospholipid, in the presence of a cellulosic derivative and/or a polymeric material belonging to the groups of oligo and polysaccharides, linear and/or cross-linked polymers of N-vinyl-2-pyrrolidone, linear polymers of vinyl alcohol, polymers of vinyl acetate, co-polymers of methacrylic acid and ethyl acrylate, co-polymers of ethylene oxide and propylene oxide, polyethylene glycols.

Description

  • The present invention relates to solid dispersions comprising Coenzyme Q10 and phospholipids, to a process for their preparation and to pharmaceutical, nutraceutical and cosmetic compositions containing them.
  • Coenzyme Q10, also known as ubidecarenone or ubiquinone, is a lipophilic endogenous substance present in most eukaryotic cells, primarily concentrated in mitochondria. Coenzyme Q10 participates to the mitochondrial oxido-reductive reactions of electron transport chain for the generation of energy, in the form of Adenosine Triphosphate (ATP). Coenzyme Q10 can exist in three oxidation states: (1) the fully reduced form (ubiquinol), (2) the radical intermediate form (semiquinone), and (3) the fully oxidized form (ubiquinone). Coenzyme Q10 exists in our body in all these forms and a physiological equilibrium between the oxidized and the reduced form is maintained.
    Figure imgb0001
  • The name ubidecarenone or ubiquinone (or ubiquinol for the reduced form) is related to the fact that Coenzyme Q10 is ubiquitously distributed in the organs of the human body, but it is primarily concentrated in organs with a higher energy requirement, like heart, liver and kidney.
  • The name ubiquinone also refers to its quinone structure, while the number 10 is the number of isoprenyl units in its tail.
  • Coenzyme Q10 can also be introduced in human body with the diet, even if the contribution of endogenous Coenzyme Q10 to its physiological plasma levels has not been clarified. The richer sources of dietary Coenzyme Q10 include meat, poultry and fish, while fruits, vegetables and eggs are limited sources of Coenzyme Q10.
  • As Coenzyme Q10 deficiency is a rare, oral coenzyme Q10 supplementation is mainly used to maintain homeostasis of the body, to promote heart health, as energy booster and also to treat different diseases like ageing, periodontal disease, impaired memory, fatigue, coronary disease, high blood pressure, immune system impairment.
  • Coenzyme Q10 supplementation can be particularly useful for elderly people, as the tissue and plasma physiological levels of Coenzyme Q10 are reported to decline with age.
  • Coenzyme Q10 is a yellow-orange crystalline powder, with a low melting point (about 50°C).
  • The activity of Coenzyme Q10 supplementation can be strongly limited by its poor pharmacokinetic properties and, in particular, by its very low oral bioavailability, due to the fact that Coenzyme Q10 is commercialized in a totally crystalline form and it is characterized by high lipophilicity and relatively high molecular weight.
  • Several formulation approaches have been applied to promote CoQ10 bioavailability, including self-emulsifying delivery systems, inclusion in cyclodextrins, solid dispersion, lipophilic formulations, microspheres, nanoparticles, etc., but absorption of Coenzyme Q10 into the systemic circulation still remains a challenge.
  • It has now been found that preparing a solid dispersion of Coenzyme Q10 and phospholipids, in the presence of other ingredients such as cellulose derivatives (methylcellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose, microcrystalline cellulose, and the like) and/or other polymeric materials including but not limited to polyvinylpyrrolidone, polyvinyl acetate, poly (methacrylic acid, methyl methacrylate), poloxamers and the like , allows a high degree of amorphization of Coenzyme Q10, determining an increased solubility, a faster dissolution rate and hence a better oral bioavailability.
  • The above mentioned cellulosic derivatives and other polymeric materials can contribute to stabilize the amorphous form of Coenzyme Q10 in order to avoid its recrystallization in the less bioavailable crystalline form.
  • The role of phospholipids may not be limited to facilitate the dispersion of Coenzyme Q10 in the gastro-intestinal fluids, but can also have the effect of enhancing the capacity of Coenzyme Q10 to cross the lipid-rich biomembranes and to reach the circulation.
  • These solid dispersions are also characterized by suitable technological properties to be easily incorporated in different dosage forms to allow an easy administration.
  • The present invention relates to a solid dispersion comprising Coenzyme Q10 and a phospholipid,
    in the presence of a cellulosic derivative and/or a polymeric material belonging to the groups of oligo and polysaccharides, linear and/or cross-linked polymers of N-vinyl-2-pyrrolidone, linear polymers of vinyl alcohol, polymers of vinyl acetate, co-polymers of methacrylic acid and ethyl acrylate, co-polymers of ethylene oxide and propylene oxide, polyethylene glycols.
  • The phospholipid may be selected from the group consisting of lecithins from soy, sunflower or egg, phosphatidyl choline, phosphatidyl serine, phosphatidyl ethanolamine, in which the acyl groups may be the same or different are mostly derived from palmitic, stearic, oleic, linoleic, linolenic acids.
  • The cellulosic derivative may be selected from the group consisting of carboxymethyl cellulose, methylcellulose, ethyl cellulose, hydroxypropylcellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, microcrystalline cellulose, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate.
  • The polymeric material may be selected from the group consisting of polyvinylpyrrolidone, polyvinyl acetate, poly (methacrylic acid, methyl methacrylate), poloxamers, chitosan, alginates, hyaluronic acid, pectin, pullulan, cyclodextrins, starch polymers, D-alpha-tocopheryl polyethylene glycol 1000 succinate.
  • In the present invention, all ratios are weight ratios.
  • The Coenzyme Q10/phospholipid ratio is preferably 0.2 to 2, most preferably 0.5 to 1.
  • The Coenzyme Q10 to cellulosic derivative ratio is preferably 0.2 to 2, most preferably 0.5 to 1.
  • The Coenzyme Q10to polymeric material ratio is 0.2 to 10, most preferably 0.5 to 5.
  • The solid dispersions of the invention provide Coenzyme Q10 with an increased degree of amorphization and a reduced tendency to recrystallize in a less bioavailable form. The solid dispersions have improved the technological properties facilitating the incorporation of the complex in different pharmaceutical, nutraceutical and cosmetic formulations.
  • The solid dispersions, according to the present invention, are prepared by reacting a solution of Coenzyme Q10 in ethyl acetate with a suspension of phospholipids in the same solvent in presence of the cellulosic derivatives and of other polymeric substances. The weight ratio of Coenzyme Q10 to phospholipids is in the range of 0.20 to 2 and more preferably in the range of 0.5 to 1. After the reaction, the compound is isolated by removing the solvent under vacuum.
  • The obtained powder is then calibrated and eventually grinded to obtain the desired particle size distribution.
  • The obtained solid dispersions were analyzed for HPLC content of Coenzyme Q10, for water content and for residual solvent.
  • A calorimetric analysis by Differential Scanning Calorimetry (DSC) was also performed to calculate, on the basis of the reduction of the enthalpy of fusion (J/g), the degree of amorphization of Coenzyme Q10 in the solid dispersion, in comparison with the totally crystalline Coenzyme Q10.
  • It has been found that the phospholipids dispersions disclosed in the present invention are characterized by a high level of amorphization of Coenzyme Q10. The amorphization of Coenzyme Q10 combined with the positive effect of phospholipids to enhance the capacity of molecules to cross the lipid-rich biomembranes, can play a synergistic effect providing a higher oral bioavailability.
  • Another object of the invention are formulations for oral administration containing the solid dispersions of the invention and pharmaceutically and food acceptable materials such as an excipient, disintegrant, lubricant, binder, coating agent, colorant, absorption promoter, solubilizing agent, stabilizer, flavor, sweetener, antiseptic, preservative, antioxidant and the like.
  • Examples of dosage forms of the formulations of the invention include, without limitation, chewable tablets, capsules, soft gelatin capsules, hard gelatin capsules, caplets, lozenges, chewable lozenges, health bars, confections, animal feeds, cereals, cereal coatings, and combinations thereof. The preparation of the above dosage forms are well known to persons of ordinary skill in the art.
  • The composition for oral administration of the present invention can be used for a variety of purposes for improving the quality of life (QOL) of humans, including the prevention and treatment for various diseases, reduction of side reactions, promotion of recovery from disease and the like, and can also be used for the purpose of maintaining and promoting daily health and the like. The dosage of the composition for oral administration of the present invention is not subject to limitation, and is preferably 1 to 1200 mg per day for a human, based on the amount of Coenzyme Q10, more preferably 10 to 800 mg, and from the viewpoint of routine ingestion and onset of effects, it is particularly preferably 30 to 500 mg. The above-described daily amount can be taken at one time or in several divided portions. Duration of ingestion is not subject to limitation.
  • The oral bioavailability of the solid dispersion of Coenzyme Q10 was evaluated in rats in comparison with Coenzyme Q10 administered as crystalline powder. The preliminary results show an improved oral bioavailability of the solid dispersion of Coenzyme Q10 with phospholipids in comparison with unformulated Coenzyme Q10.
  • The present invention also relates to pharmaceutical, nutraceutical and cosmetic compositions containing one of the phospholipids complexes of Coenzyme Q10 according to the present invention as the active principle, in admixture with suitable pharmaceutical, nutraceutical and cosmetic carriers.
    • EXAMPLES Example 1 - Preparation of the solid dispersion
  • 1.5 Kg of microcrystalline cellulose, 2.0 Kg of sunflower lecithin and 0.5 Kg of cellulose ethers (methyl cellulose and hydroxypropylmethyl cellulose) were suspended in 50 liters of ethyl acetate and refluxed for one hour. The resulting suspension was cooled to 40°C.
  • 1 Kg of Coenzyme Q10 was dissolved in 30 liters of ethyl acetate at 20-25°C in the dark. The obtained solution was filtered and added to the suspension of microcrystalline cellulose, sunflower lecithin and cellulose ethers. The obtained suspension was stirred at 40°C for about one hour.
  • The solvent was then removed under reduced pressure until a soft mass was obtained. The latter was dried at 50°C under vacuum for 16 hours, until a residual of Ethyl acetate lower than 5000 ppm.
  • The resulting solid was calibrated through a 2 mm screen to obtain a yellow-orange solid
    • Example 2 - Characterization of the solid dispersion: Differential Scanning Calorimetry
  • The solid dispersion of Coenzyme Q10 with phospholipid was analyzed by Differential Scanning Calorimetry (DSC) in comparison with crystalline Coenzyme Q10.
  • The analyses were performed using a Mettler DSC1 System. Heat flow was recorded from 30 to 300°C with linear heating rate (10°C/min), using closed aluminium crucibles (40 µl volume) with a pinhole, under a 50 ml/min nitrogen flow.
  • About 5-10 mg of powder were used for each measurement. The thermal profiles were acquired and elaborated by a dedicated software.
  • The degree of amorphization of Coenzyme Q10 in the solid dispersion was in the range 30-40% and it was calculated on the basis of the reduction of the enthalpy of fusion.
    • Example 3 - Pharmacokinetic study in rats
  • Pharmacokinetic parameters (Tmax, Cmax, absolute bioavailability) were determined in rats after the oral administration of a single dose of Coenzyme Q10 as crystalline powder and as solid dispersion with phospholipids.
  • Male Sprague-Dawley rats, weighting 300-350 g were used for the pharmacokinetic experiment. Rats were fasted 16 hours before administration with free access to water.
  • Coenzyme Q10 as crystalline powder and as solid dispersion with phospholipids were suspended in 1% carboxymethyl cellulose water suspension and administered by intragastric gavage as a single dose of 50 mg of Coenzyme Q10/Kg.
  • Blood samples were collected from tail vein after 0.5 - 1.0 - 2.0 - 4.0 - 8.0 - 12.0 and 24 hours after administration.
  • Plasma was obtained from blood samples by centrifugation at 5.000 x g for 15 minutes and kept frozen (-20°C) until analysis. After protein sedimentation, Coenzyme Q10 was extracted by plasma samples with n-hexane; the extraction step with hexane was repeated for three times. The hexane phases, separated by centrifugation, were collected and the solvent was removed by evaporation under nitrogen. The residue was dissolved in 2-propanol for HPLC/MS analysis at 275 nm, using internal standard method for Coenzyme Q10 quantification.
  • The following pharmacokinetic parameters were calculated:
    Parameter Crystalline Coenzyme Q10 Coenzyme Q10 solid dispersion with phospholipids
    Tmax (hours) 3.8 4.0
    Cmax (µg/ml) 0.23 1.35
    AUC 0-24 (µg h/ml) 4.1 29.2
    • Example 4 - Formulations containing the solid dispersion of Coenzyme Q 10 with phospholipid (film-coated tablets)
  • Coenzyme Q10 solid dispersion 400.0 mg
    Microcrystalline cellulose 200.0 mg
    Dicalcium phosphate anhydrous 146.0 mg
    Sodium croscarmellose 30.0 mg
    Silicon dioxide 8.0 mg
    Talc 8.0 mg
    Magnesium stearate 8.0 mg
    Film-coating 20.0 mg
    • Example 5 - Formulation containing the solid dispersion of Coenzyme Q 10 with phospholipids (soft gelatin capsules)
  • Coenzyme Q10 solid dispersion 250.0 mg
    Flaxseed oil 384.0 mg
    Glyceryl monostearate 10.0 mg
    Lecithin 6.0 mg

Claims (11)

  1. A solid dispersion comprising Coenzyme Q10 and a phospholipid, in the presence of a cellulosic derivative and/or a polymeric material belonging to the groups of oligo and polysaccharides, linear and/or cross-linked polymers of N-vinyl-2-pyrrolidone, linear polymers of vinyl alcohol, polymers of vinyl acetate, co-polymers of methacrylic acid and ethyl acrylate, co-polymers of ethylene oxide and propylene oxide, polyethylene glycols.
  2. The solid dispersion according to claim 1 wherein the phospholipid is selected from the group consisting of lecithins from soy, sunflower or egg, phosphatidyl choline, phosphatidyl serine, phosphatidyl ethanolamine, in which the acyl groups may be the same or different are mostly derived from palmitic, stearic, oleic, linoleic, linolenic acids.
  3. The solid dispersion according to claim 1 wherein the cellulosic derivative is selected from the group consisting of carboxymethyl cellulose, methylcellulose, ethyl cellulose, hydroxypropylcellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, microcrystalline cellulose, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate.
  4. The solid dispersion according to claim 1 wherein the polymeric material is selected from the group consisting of polyvinylpyrrolidone, polyvinyl acetate, poly (methacrylic acid, methyl methacrylate), poloxamers, chitosan, alginates, hyaluronic acid, pectin, pullulan, cyclodextrins, starch polymers, D-alpha-tocopheryl polyethylene glycol 1000 succinate.
  5. The solid dispersion according to anyone of claims 1-4 wherein the Coenzyme Q10 to phospholipid ratio is 0.2 to 2.
  6. The solid dispersion according to claim 5 wherein the Coenzyme Q10 to phospholipid ratio is 0.5 to 1.
  7. The solid dispersion according to anyone of claims 1-4 wherein the Coenzyme Q10 to cellulosic derivative ratio is 0.2 to 2.
  8. The solid dispersion according to claim 7 wherein the Coenzyme Q10 to cellulosic derivative ratio is 0.5 to 1.
  9. The solid dispersion according to anyone of claims 1-4 wherein the Coenzyme Q10 to polymeric material ratio is 0.2 to 10.
  10. The solid dispersion according to claim 9 wherein the Coenzyme Q10 to polymeric material ratio is 0.5 to 5.
  11. A pharmaceutical or nutraceutical formulation for oral administration containing a solid dispersion according to any one of claims 1-10 and a pharmaceutically or food acceptable excipients.
EP15171943.2A 2015-06-12 2015-06-12 Solid dispersions of coenzyme q10 Withdrawn EP3103440A1 (en)

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EP15171943.2A EP3103440A1 (en) 2015-06-12 2015-06-12 Solid dispersions of coenzyme q10
US15/579,975 US10905657B2 (en) 2015-06-12 2016-06-10 Solid dispersions of Coenzyme Q10
CN201680032963.7A CN107750158B (en) 2015-06-12 2016-06-10 Solid dispersion of coenzyme Q10
JP2017563338A JP6910309B2 (en) 2015-06-12 2016-06-10 Solid dispersion of coenzyme Q10
HUE16732249A HUE047668T2 (en) 2015-06-12 2016-06-10 Solid dispersions of coenzyme q10
PL16732249T PL3307244T3 (en) 2015-06-12 2016-06-10 Solid dispersions of coenzyme q10
ES16732249T ES2768950T3 (en) 2015-06-12 2016-06-10 Coenzyme Q10 solid dispersions
KR1020177035183A KR20180017016A (en) 2015-06-12 2016-06-10 Solid dispersion of Coenzyme Q10
PT167322494T PT3307244T (en) 2015-06-12 2016-06-10 Solid dispersions of coenzyme q10
CA2988478A CA2988478C (en) 2015-06-12 2016-06-10 Solid dispersions of coenzyme q10
SI201630621T SI3307244T1 (en) 2015-06-12 2016-06-10 Solid dispersions of coenzyme q10
BR112017026291-6A BR112017026291B1 (en) 2015-06-12 2016-06-10 SOLID DISPERSIONS, PHARMACEUTICAL OR NUTRACEUTICAL FORMULATIONS AND METHOD FOR PREPARING A SOLID DISPERSION
EP16732249.4A EP3307244B1 (en) 2015-06-12 2016-06-10 Solid dispersions of coenzyme q10
AU2016274662A AU2016274662B2 (en) 2015-06-12 2016-06-10 Solid dispersions of Coenzyme Q10
DK16732249.4T DK3307244T3 (en) 2015-06-12 2016-06-10 Solid dispersions of coenzyme 10
PCT/EP2016/063262 WO2016198576A1 (en) 2015-06-12 2016-06-10 Solid dispersions of coenzyme q10
RU2017142563A RU2742579C2 (en) 2015-06-12 2016-06-10 Solid dispersions q10
IL256159A IL256159B (en) 2015-06-12 2017-12-06 Solid dispersions of coenzyme q10
HK18110196.1A HK1250652A1 (en) 2015-06-12 2018-08-08 Solid dispersions of coenzyme q10

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US11708463B2 (en) 2018-04-06 2023-07-25 Capsugel Belgium Nv Spray drying process for low aspect ratio particles comprising poly[(methyl methacrylate)-co-(methacrylic acid)]
CN111374965B (en) * 2018-12-28 2024-01-16 上海融澈水性材料有限公司 Water-soluble coenzyme Q10 inclusion compound with high stability and preparation method thereof
IT201900003907A1 (en) 2019-03-18 2020-09-18 Indena Spa COMPOSITIONS INCLUDING CURCUMIN AND COENZYME Q10
WO2021040027A1 (en) * 2019-08-30 2021-03-04 三栄源エフ・エフ・アイ株式会社 Solid composition containing amorphous, poorly water-soluble material, and method for producing same
KR20220054378A (en) * 2019-08-30 2022-05-02 산에이겐 에후.에후. 아이. 가부시키가이샤 Solid composition containing amorphous poorly water-soluble material and method for producing the same
CN117837754B (en) * 2024-03-08 2024-05-28 中国农业大学 Amorphous coenzyme Q10 with improved solubility and preparation method thereof

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CN107750158A (en) 2018-03-02
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PL3307244T3 (en) 2020-05-18
RU2017142563A3 (en) 2019-11-28
AU2016274662B2 (en) 2020-08-20
EP3307244A1 (en) 2018-04-18
SI3307244T1 (en) 2020-03-31
US20180200201A1 (en) 2018-07-19
RU2017142563A (en) 2019-07-12
BR112017026291A2 (en) 2018-09-11
CA2988478A1 (en) 2016-12-15
KR20180017016A (en) 2018-02-20
EP3307244B1 (en) 2019-11-20
HUE047668T2 (en) 2020-05-28
WO2016198576A1 (en) 2016-12-15
IL256159B (en) 2020-06-30
US10905657B2 (en) 2021-02-02
CA2988478C (en) 2023-10-03
DK3307244T3 (en) 2020-02-24
RU2742579C2 (en) 2021-02-08
JP2018516945A (en) 2018-06-28
IL256159A (en) 2018-02-28
AU2016274662A1 (en) 2018-01-04
ES2768950T3 (en) 2020-06-24
PT3307244T (en) 2020-02-03
CN107750158B (en) 2021-08-27

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